Spinal cord injury (SCI) leads to a profound reduction in physical activity, resulting in a low exercise capacity and increased risk of mortality. Of note, physical inactivity is approaching tobacco as the leading actual cause of death in the able-bodied population and people with SCI are at a much greater risk of dying of cardiovascular disease than their able-bodied counterparts. To counteract the effects of cardiovascular disease, it is imperative that we find effective methods of exercise that people with SCI can perform on a routine basis. Neuromuscular electrical stimulation (NMES) is the only available tool to activate paralyzed skeletal muscles to perform functional activities. Previous studies examining NMES-induced exercise have successfully improved skeletal muscle size and physiological properties, thus decreasing health-related risks. However, these studies have been limited to small samples of men. In this proposal, the PIs aim to study skeletal muscle responses of both males and females with SCI to NMES-induced exercise, leading to the long-term goal of the establishment of exercise programs that incorporate NMES to effectively increase physical activity for all persons after SCI, thereby reducing chronic disease and mortality rates. Gender is an important factor in multiple health-related fields of study, including but not limited to: cardiovascular disease, cancer, and susceptibility to orthopedic injury. As such, gender-specific treatment approaches have been developed to most effectively combat these problems. Interestingly, studies examining skeletal muscle in persons with SCI often exclude females, or they otherwise represent an extremely small proportion of the overall sample. Studies in able-bodied subjects have demonstrated that males are more fatigable than their female counterparts during voluntary exercise. However, little attention has been given to the impact that gender has on skeletal muscle responses to NMES in persons with or without SCI. Given that gender reportedly influences neurological and functional recovery after SCI, it would be naive to simply assume that gender does not affect skeletal muscle responses to NMES after SCI. If one is to continue investigating the potential of NMES exercise, one must first determine 1) the influence of gender on response to NMES in persons with SCI and 2) the basis for prescription of optimal stimulation parameters during NMES-induced exercise regimes. Public Health Relevance: Spinal cord injury (SCI) is a devastating condition that results in a dramatic reduction in physical activity. Muscle fatigue is a major issue related to the efficacy of neuromuscular electrical stimulation (NMES) to improving activity levels. The overarching aim of this application is to improve NMES protocols for all patients with disabilities, with special attention to gender related differences in muscle fatigue.